1. Field of Invention
The present invention relates generally to improvements in technology used in the field of vascular occlusions of the respiratory system, and more particularly to non-invasive devices and methods for the diagnosis of a pulmonary embolism and related disorders.
2. Description of Prior Art
A pulmonary embolism occurs when an embolus becomes lodged in lung arteries, thus blocking blood flow to lung tissue. An embolus is usually a blood clot, known as a thrombus, but may also comprise fat, amniotic fluid, bone marrow, tumor fragments, or even air bubbles that block a blood vessel. Unless treated promptly, a pulmonary embolism can be fatal. In the United States alone, around 600,000 cases occur annually, 10 percent of which result in death.
The detection of a pulmonary embolism is extremely difficult because signs and symptoms can easily be attributed to other conditions and symptoms may vary depending on the severity of the occurrence. Frequently, a pulmonary embolism is confused with a heart attack, pneumonia, hyperventilation, congestive heart failure or a panic attack. In other cases, there may be no symptoms at all.
Often, a physician must first eliminate the possibility of other lung diseases before determining that the symptoms, if any, are caused by a pulmonary embolism. Traditional diagnostic methods of testing involve blood tests, chest X-rays, and electrocardiograms. These methods are typically more effective in ruling out other possible reasons than for actually diagnosing a pulmonary embolism. For example, a chest x-ray may reveal subtle changes in the blood vessel patterns after an embolism and signs of pulmonary infarction. However, chest x-rays often show normal lungs even when an embolism is present, and even when the x-rays show abnormalities they rarely confirm a pulmonary embolism. Similarly, an electrocardiogram may show abnormalities, but it is only useful in establishing the possibility of a pulmonary embolism.
As a pulmonary embolism alters the ability of the lungs to oxygenate the blood and to remove carbon dioxide from the blood, one method of diagnosing the condition involves taking a specimen of arterial blood and measuring the partial pressure of oxygen and carbon dioxide in the arterial blood (i.e., an arterial blood gas analysis). Although a pulmonary embolism usually causes abnormalities in these measurements, there is no individual finding or combination of findings from the arterial blood gas analysis that allows either a reliable way to exclude or specific way of diagnosing pulmonary embolism. In particular, at least 15-20% of patients with a documented pulmonary embolism have normal oxygen and carbon dioxide contents of the arterial blood. Accordingly, the arterial blood analysis cannot reliably include or exclude the diagnosis of a pulmonary embolism.
The blood D-dimer assay is another diagnostic method that has become available for commercial use. The D-dimer protein fragment is formed when fibrin is cleaved by plasmin and therefore produced naturally whenever clots form in the body. As a result, the D-dimer assay is extremely sensitive for the presence of a pulmonary embolism but is very nonspecific. In other words, if the D-dimer assay is normal, the clinician has a reasonably high degree of certainty that no pulmonary embolism is present. However, many studies have shown a D-dimer assay is only normal in less than ⅓ of patients and thus produces a high degree of false positives. As a result, the D-dimer assay does not obviate formal pulmonary vascular imaging in most patients with symptoms of a pulmonary embolism.
In an attempt to increase the accuracy of diagnostic, physicians have recently turned to methods which can produce an image of a potentially afflicted lung. One such method is a nuclear perfusion study which involves the injection of a small amount of radioactive particles into a vein. The radioactive particles then travel to the lungs where they highlight the perfusion of blood in the lung based upon whether they can penetrate a given area of the lung. While normal results can indicate that a patient lacks a pulmonary embolism, an abnormal scan does not necessarily mean that a pulmonary embolism is present. Nuclear perfusion is often performed in conjunction with a lung ventilation scan to optimize results.
During a lung ventilation scan, the patient inhales a gaseous radioactive material. The radioactive material becomes distributed throughout the lung's small air sacs, known as alveoli, and can be imaged. By comparing this scan to the blood supply depicted in the perfusion scan, a physician may be able to determine whether the person has a pulmonary embolism based upon areas that show normal ventilation but lack sufficient perfusion. Nevertheless, a perfusion scan does not always provide clear evidence that a pulmonary embolism is the cause of the problem as it often yields indeterminate results in as many as 70% of patients.
Pulmonary angiograms are popular means of diagnosing a pulmonary embolism, but the procedure poses some risks and is more uncomfortable than other tests. During a pulmonary angiogram, a catheter is threaded into the pulmonary artery so that iodine dye can be injected into the bloodstream. The dye flows into the regions of the lung and is imaged using x-ray technology, which would indicate a pulmonary embolism as a blockage of flow in an artery. Pulmonary angiograms are more useful in diagnosing a pulmonary embolism than some of the other traditional methods, but often present health risks and can be expensive. Although frequently recommended by experts, few physicians and patients are willing to undergo such an invasive procedure.
Spiral volumetric computed tomography is another diagnostic tool that has recently been proposed as a less invasive test which can deliver more accurate results. The procedure's reported sensitivity has varied widely, however, and it may only be useful for diagnosing an embolism in central pulmonary arteries as it is relatively insensitive to clots in more remote regions of the lungs.
These pulmonary vascular imaging tests have several disadvantages in common. Nearly all require ionizing radiation and invasiveness of, at a minimum, an intravenous catheter. The imaging tests also typically involve costs of more than $1,000 for the patient, take more than two hours to perform, and require special expertise such as a trained technician to perform the tests and acquire the images and a board-certified radiologist to interpret the images. Notably, none are completely safe for patients who are pregnant. As a result of these shortcomings, the imaging procedures are not available in many outpatient clinic settings and in many portions of third world countries.
Nitric oxide (NO) is a clear colorless gas, produced naturally by enzymatic action on endogenous amino acids and molecular oxygen. Nitric oxide causes dilation of blood vessels, including the precapillary pulmonary arteries. It is well established that NO production generally increases in a plurality of mammalian tissues in response to a plurality of insults. Acute pulmonary embolism that causes obstruction of the pulmonary arteries represents a notable exception. Pulmonary embolism also causes direct obstruction of pulmonary vasculature, which leads to immediate elevation in pulmonary arterial pressures. This increase in pressure causes greater hydraulic shear forces to be exerted on erythrocytes as they are pumped out of the right ventricle into the lung and through the open lung arteries. Increased shear forces cause intravascular, intrapulmonary hemolysis, which leads to a release of free hemoglobin. The heme moiety of hemoglobin can bind NO, thereby causing a decrease in the concentration of NO in expired breath. Free hemoglobin is eventually degraded by intrapulmonary macrophages, through a catabolic pathway that liberates bilirubin and CO. Thus, intrapulmonary hemolysis consequent to pulmonary vascular obstruction causes decrease in lung NO content and an increase in CO content.
Testing also suggests that induction of either mild or severe pulmonary vascular occlusion in rats causes no increase in the transcription of the enzyme inducible nitric oxide synthase, the enzyme primarily responsible for producing nitric oxide in lung tissues. However, pulmonary vascular occlusion causes a dose-dependent increase in transcription of heme-oxygenase, also known as HO-1. Heme-oxygenase is the primary endogenous source of carbon monoxide (CO).
It is well established that exhaled concentrations of NO increase with many types of inflammatory lung disease, while the exhaled concentrations of CO have a more variable response, to some extent depending upon whether the patient is a smoker. In general, few diseases cause a simultaneous decrease in NO and increase in CO. A notable exception is the effect of smoking in the setting of chronic obstructive lung disease (COPD). This combination is known to decrease NO and increase CO. However, COPD produces a specific pattern and slope of the expired CO2, 02, and CO2/O2 ratio when these values are plotted as a function of expired volume on a dynamic basis. Mathematical and visual analysis of these curves allow distinction of COPD and other causes of airway obstruction from pulmonary vascular occlusion. A key drawback to the isolated measurement of NO is its lack of correspondence with clinical severity. The addition of the measurement of the CO2/O2 ratio as an index of hypoventilation, together with the dynamic plot of this ratio will improve the diagnostic accuracy of exhaled NO.
Moreover, certain treatments for a patient with pulmonary vascular occlusions are aimed at increasing concentrations of NO in both the acute and chronic setting. Pulmonary vascular occlusion can be associated with regional pre-capillary vascoconstriction, a reversible process that worsens the severity of mechanical pulmonary vascular obstruction. Pharmacological agents can be infused, ingested or inhaled that are specifically designed to enhance the intrapulmonary concentration and vasodilatory effect of NO in the lung vasculature. Continuous measurement of the CO2:O2 ratio while “spot checking” the expired NO concentration will provide a method to simultaneously determine bioavailability and physiological response of the lung to an treatment designed to increase intrapulmonary NO concentration for a patient with a process causing pulmonary vascular occlusion (see, e.g, U.S. Pat. No. 5,968,911 to Lawson, U.S. Pat. No. 5,839,433 to Higenbottam, and U.S. Pat. No. 5,823,180 to Zapol). Typical exhaled concentrations of NO associated with a therapeutic response are in the 10-300 parts per million range, whereas an increase in the CO2:O2 ratio above 40% (0.40) is associated with decrease in pulmonary vascular resistance.
Exhaled ozone (O3) represents an additional inorganic molecule that indicates airway inflammation. Ozone inhaled from the ambient atmosphere is known to induce oxidative damage to lungs, and the amount of inhaled ozone increases in proportion to isprenoid markers of airway inflammation. In this classic scenario, the exhaled concentration of ozone is lower than the inhaled concentration, reflecting the consumption of ozone during oxidation of lung tissue substrates. However, under certain pathological conditions marked by oxidant damage, the lung may produce ozone, such that the exhaled concentration exceeds the inhaled concentration.
At least one device measures expired NO using laser spectroscopy. This device reports the concentration of NO and the concentration of CO2 per breath for the purpose of diagnosing asthma exacerbations. The device does not measure CO, or O2, however, and does not compute and display the concentration of NO as a function of the CO2/O2, or vise versa, either on a dynamic breath-to-breath basis or as an average point estimate.